Cancer remains the second leading cause of death in the United States. It is estimated that over 560,000 individuals in the US will die from cancer during 2004 and 1,368,030 new cases will be diagnosed. Historically, natural products or compounds modeled on them, have found significant utility in the treatment of cancer. A number of marine-derived compounds are currently under clinical investigation for the treatment of cancer, including discodermolide, a compound discovered at HBOI from a deep-water sponge, and brought to the clinic by Novartis. Advances in our understanding of neoplastic progression have provided new targets for intervention in cancer and the discovery of compounds which selectively act on these targets has begun to provide novel therapies with limited, if any, side effects. In this proposal we will continue to substantiate our hypothesis that marine natural products (MNPs) can be discovered which interact at these defined molecular targets and that these compounds, or compounds modeled upon them, will be useful in the treatment of cancer. The project will be carried out in collaboration with the Novartis Institute of Biomedical Research, Inc. (NIBRI), the Crews MNP group at UC Santa Cruz (UCSC), the Gerwick group at Oregon State University (OSU) and the Fenical group at Scripps Institute of Oceanography (SIO). HBOI brings to the NCDDG a complementary set of organisms and expertise. The Specific Aims for this Project are as follows: 1. To create a diverse and complementary library of highly enriched fractions/pure materials ("a peak library") derived from Atlantic and Caribbean marine organisms. 2. To submit the materials to NIBRI for assay in their panel of epigenetic and molecular screens and use these assays to follow purification when necessary. 3. To utilize state-of-the-art MS and NMR techniques for rapid and accurate dereplication and structure elucidation of candidate compounds. 4. To provide sufficient compound to the NIBRI to allow for secondary biological testing and follow up.